Laboratory of Inflammation and Immunology, Guarulhos University, Guarulhos, Brazil.
Department of Physiological Sciences, Piracicaba Dental School, University of Campinas, Piracicaba, Brazil.
Curr Drug Deliv. 2020;17(7):588-598. doi: 10.2174/1567201817666200512101448.
Antiproliferative and cytotoxic effects of lidocaine have been reported in tumor cells. However, the use of these drugs is restricted due to their short action with rapid dispersion from the injected site. The complexation of local anesthetics in 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) is able to improve pharmacological features.
This study evaluated the antitumor effects of lidocaine and the complex HP-β-CD-lidocaine (HP-β-CD-lido).
In vitro;, human adenocarcinoma (HeLa) and keratinocytes (HaCaT) were exposed to lidocaine formulations and cell viability, proliferation and apoptosis induction were measured. In vivo;, Walker 256 carcinoma cells were subcutaneously injected into the plantar region of the rat right hind paw. The animals were treated with a local application of 5% lidocaine or 5% HP-β-CD-lido. Doxorubicin (3 mg/Kg/day, intraperitoneal) was used as a positive control. Edema sizes were measured daily and the release of cytokines (TNF-α, IL-1α and CXCL-1) and prostaglandin E2 was evaluated. Histological analysis was also performed.
HaCaT IG50 values were 846 μM and 2253 μM for lido and HP-β-CD-lido, respectively. In HeLa cells, the IG50 was 1765 μM for lido and 2044 μM for HP-β-CD-lido. Lidocaine formulations significantly reduced the paw edema on day 6 after Walker 256 cells inoculation. However, there were no differences in the release of inflammatory mediators in comparison to the control group.
Lidocaine formulations were able to reduce the edema in vivo;, without affecting the tumor- induced inflammatory response. The antiproliferative effects of lidocaine formulations may have contributed to tumor reduction.
已报道利多卡因在肿瘤细胞中具有抗增殖和细胞毒性作用。然而，由于其作用时间短且从注射部位迅速扩散，这些药物的应用受到限制。局部麻醉剂与 2-羟丙基-β-环糊精（HP-β-CD）的络合能够改善其药理特性。
本研究评估了利多卡因及其复合物 HP-β-CD-利多卡因（HP-β-CD-lido）的抗肿瘤作用。
在体外，将人腺癌（HeLa）和角质形成细胞（HaCaT）暴露于利多卡因制剂中，并测量细胞活力、增殖和凋亡诱导。在体内，将 Walker 256 癌瘤细胞皮下注射到大鼠右后爪的足底区域。动物接受 5%利多卡因或 5% HP-β-CD-lido 的局部应用治疗。阿霉素（3mg/Kg/天，腹腔内）用作阳性对照。每天测量水肿大小，并评估细胞因子（TNF-α、IL-1α 和 CXCL-1）和前列腺素 E2 的释放。还进行了组织学分析。
HaCaT 的 IG50 值分别为利多卡因 846μM 和 HP-β-CD-lido 2253μM。在 HeLa 细胞中，利多卡因的 IG50 为 1765μM，HP-β-CD-lido 为 2044μM。利多卡因制剂显著降低了 Walker 256 细胞接种后第 6 天的爪水肿。然而，与对照组相比，炎症介质的释放没有差异。
利多卡因制剂能够减少体内水肿，而不影响肿瘤诱导的炎症反应。利多卡因制剂的抗增殖作用可能有助于肿瘤缩小。
